Methods for making oxidation resistant polymeric material

ABSTRACT

The present invention relates to methods for making oxidation resistant medical devices that comprise polymeric materials, for example, ultra-high molecular weight polyethylene (UHMWPE). The invention also provides methods of making antioxidant-doped medical implants, for example, doping of medical devices containing cross-linked UHMWPE with vitamin E by diffusion and materials used therein.

This application is a continuation of U.S. application Ser. No.11/564,594 filed Nov. 29, 2006, which is a continuation of U.S.application Ser. No. 10/757,551 filed Jan. 15, 2004, now U.S. Pat. No.7,431,864, which claims the benefit of U.S. to Provisional ApplicationNo. 60/440,389 filed Jan. 16, 2003. The entire contents of theabove-identified applications are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates to methods for making oxidation resistantmedical devices that comprise polymeric materials. Methods of dopingpolyethylene with an antioxidant, for example, vitamin E, and materialsused therewith also are provided.

BACKGROUND OF THE INVENTION

Oxidation resistant cross-linked polymeric material, such as ultra-highmolecular weight polyethylene (UHMWPE), is desired in medical devicesbecause it significantly increases the wear resistance of the devices.The preferred method of crosslinking is by exposing the UHMWPE toionizing radiation. However, ionizing radiation, in addition tocrosslinking, also will generate residual free radicals, which are theprecursors of oxidation-induced embrittlement. Melting after irradiationis used to eliminate the crystals and allow the residual free radicalsto recombine with each other. The irradiation with subsequent melting isused to reduce the potential for oxidation secondary to the residualfree radicals. However, post-irradiation melting reduces thecrystallinity of UHMWPE, which, in turn, decreases the yield strength,ultimate tensile strength, modulus, and fatigue strength of UHMWPE. Forcertain applications that require high fatigue resistance, such highlycrosslinked UHMWPE (that is irradiated and melted) may not be suitable;because, fatigue failure in the long term may compromise the performanceof the medical device. Therefore, there is a need to either eliminatethe residual free radicals or the oxidative effect of residual freeradicals without melting. Such a method would preserve the crystallinityof the irradiated UHMWPE and also preserve the mechanical properties andfatigue resistance.

It is generally known that mixing of polyethylene powder with anantioxidant prior to consolidation may improve the oxidation resistanceof the polyethylene material. Antioxidants, such as vitamin E and13-carotene, have been mixed with UHMWPE powder or particles by severalinvestigators (see, Mori et al. p. 1017, Hand-out at the 47th AnnualMeeting, Orthopaedic Res Soc, Feb. 25-28, 2001, San Francisco, Calif.;McKellop et al. WO 01/80778; Schaffner et al. EP 0 995 450; Hahn D. U.S.Pat. No. 5,827,904; Lidgren et al. U.S. Pat. No. 6,448,315), in attemptsto improve wear resistance. Mori et al. also described that irradiationdoes not decrease the oxidation resistance of antioxidant-dopedpolyethylene. The investigators (see, McKellop et al. WO 01/80778;Schaffner et al. EP 0 995 450; Hahn D. U.S. Pat. No. 5,827,904; Lidgrenet al. U.S. Pat. No. 6,448,315) described mixing polyethylene powderwith antioxidants, followed by consolidating the antioxidant-powder mixto obtain oxidation resistant polyethylene. Mixing of the resin powder,flakes, or particles with vitamin E and consolidation thereafter resultin changes in color of polymeric material to yellow (see for example,U.S. Pat. No. 6,448,315). In addition, the addition of the antioxidantto the UHMWPE prior to irradiation can inhibit crosslinking of theUHMWPE during irradiation. However, crosslinking is needed to increasethe wear resistance of the polymer. Therefore, it would be preferable tohave a medical implant, or any polymeric component thereof, doped withan antioxidant in its consolidated solid form, such as feed-stock,machined components, or molded components. However, this was notpossible with prior art practices.

SUMMARY OF THE INVENTION

The present invention relates generally to methods of making oxidationresistant medical devices that comprises one or more polymericmaterials. More specifically, the invention relates to methods ofmanufacturing antioxidant doped medical devices containing cross-linkedpolyethylene, for example, cross-linked ultra-high molecular weightpolyethylene (UHMWPE), and materials used therein. More specifically,the invention relates to methods of manufacturing antioxidant-doped,non-oxidizing medical device containing cross-linked polyethylene withresidual free radicals, for example, irradiated ultra-high molecularweight polyethylene (UHMWPE) and materials used therein.

In one aspect, the invention provides methods of making cross-linkedpolymeric material comprising the steps of: a) providing consolidatedand cross-linked polymeric material that has been irradiated withionizing radiation; and b) doping the consolidated and cross-linkedpolymeric material with an antioxidant by diffusion.

In another aspect, the invention provides methods of making cross-linkedpolymeric material comprising the steps of: a) providing consolidatedand cross-linked polymeric material that has been irradiated withionizing radiation; b) doping the consolidated and cross-linkedpolymeric material with an antioxidant by diffusion; and c) heating theconsolidated and cross-linked polymeric material to a temperature belowthe melting point of the consolidated and cross-linked polymericmaterial.

In another aspect, the invention provides methods of making cross-linkedpolymeric material, wherein the cross-linked polymeric material issoaked in a solution, of about 50% by weight, of an antioxidant in analcohol, such as ethanol, wherein the cross-linked polymeric material isdiffused with the antioxidant in a supercritical fluid, such as CO₂.

In another aspect, the invention provides methods of making cross-linkedpolymeric material comprising the steps of: a) placing a consolidatedand cross-linked polymeric material in a pressure chamber; b) fillingthe chamber with an antioxidant, either in a neat form (about 100%) orin a solution such as a 50% mixture of the antioxidant and alcohol, suchas ethanol; and c) pressurizing the chamber to enhance diffusion of theantioxidant into the consolidated and cross-linked polymeric material.

In another aspect, the invention provides methods of making cross-linkedpolymeric material comprising the steps of: a) doping the consolidatedpolymeric material with an antioxidant by diffusion; b) irradiating theconsolidated polymeric material with ionizing radiation, thereby forminga consolidated and cross-linked polymeric material; and c) annealing theconsolidated and cross-linked polymeric material at a temperature belowor above melt of the consolidated and cross-linked polymeric material.

According to another aspect, the invention provides methods of makingcross-linked polymeric material, comprising the steps of: a)consolidating a polymeric material; b) irradiating the polymericmaterial with ionizing radiation, thereby forming a to consolidated andcross-linked polymeric material; c) doping the consolidated andcross-linked polymeric material with an antioxidant by diffusion; and d)heating the consolidated and cross-linked polymeric material at atemperature below the melting point of the consolidated and cross-linkedpolymeric material.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) irradiating the consolidated polymericmaterial with ionizing radiation, thereby forming a consolidated andcross-linked polymeric material; d) machining the consolidated andcross-linked polymeric material, thereby forming a medical implant; ande) doping the medical implant with an antioxidant by diffusion, therebyforming an antioxidant-doped cross-linked medical implant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a consolidated polymeric material; b)irradiating the consolidated polymeric material with ionizing radiation,thereby forming a consolidated and cross-linked polymeric material; c)machining the consolidated and cross-linked polymeric material, therebyforming a medical implant; and d) doping the medical implant with anantioxidant by diffusion, thereby forming an antioxidant-dopedcross-linked medical implant.

In another aspect, the invention provides methods of making a medicalimplant containing antioxidant-doped cross-linked polymeric materialcomprising: a) irradiating a consolidated polymeric material withionizing radiation, thereby forming a cross-linked polymeric material;b) machining the consolidated and cross-linked polymeric material,thereby forming a medical implant; and c) doping the medical implantwith an antioxidant by diffusion.

In another aspect, the invention provides methods of making a medicalimplant containing antioxidant-doped cross-linked polymeric materialcomprising: a) machining a consolidated polymeric material, therebyforming a medical implant; b) doping the medical implant with anantioxidant by diffusion; and c) irradiating the medical implant,thereby forming a medical implant containing cross-linked polymericmaterial.

In another aspect, the invention provides methods of making a medicalimplant containing polymeric material comprising: a) irradiating thepolymeric material with ionizing radiation, thereby forming across-linked polymeric material; and b) doping the cross-linkedpolymeric material with an antioxidant by diffusion, wherein thecross-linked polymeric material is annealed at a temperature below themelt or above the melt of the consolidated and cross-linked polymericmaterial.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a)compression molding of polymeric material to another piece, therebyforming an interface and an interlocked hybrid material; b) irradiatingthe interlocked hybrid material by ionizing radiation, thereby forming across-linked and interlocked hybrid material; and c) doping thecross-linked and interlocked hybrid material with an antioxidant bydiffusion.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a)compression molding of polymeric material to another piece, therebyforming an interface and an interlocked hybrid material; b) doping theinterlocked hybrid material with an antioxidant by diffusion; and c)irradiating the interlocked hybrid material by ionizing radiation,thereby forming a cross-linked and interlocked hybrid material.

In another aspect, the invention provides methods of making a sterilemedical implant containing cross-linked polymeric material comprising:a) direct compression molding a polymeric material, thereby forming amedical implant; b) irradiating the medical implant to crosslink thepolymeric material; c) doping the irradiated medical implant with anantioxidant by diffusion; d) packaging the irradiated andantioxidant-doped medical implant; and e) sterilizing the packagedirradiated and antioxidant-doped medical implant by ionizing radiationor gas sterilization, thereby forming a cross-linked and sterile medicalimplant.

In another aspect, the invention provides methods of making a sterilemedical implant containing antioxidant doped cross-linked polymericmaterial comprising: a) machining a consolidated polymeric material,thereby forming a medical implant; b) irradiating the medical implant,thereby forming a medical implant containing cross-linked polymericmaterial; c) doping the medical implant with an antioxidant by todiffusion; d) packaging the irradiated and antioxidant-doped medicalimplant; and e) sterilizing the packaged medical implant by ionizingradiation or gas sterilization, thereby forming a cross-linked andsterile medical implant.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) dopinga polymeric material with an antioxidant by diffusion; b) compressionmolding of the polymeric material to another piece, thereby forming aninterface and an interlocked hybrid material; and c) irradiating theinterlocked hybrid material by ionizing radiation, thereby forming across-linked and interlocked hybrid material.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) directcompression molding of the polymeric material, thereby forming a medicalimplant; b) irradiating the medical implant by ionizing radiation,thereby forming a consolidated and cross-linked medical implant; and c)doping the consolidated and cross-linked medical implant with anantioxidant by diffusion.

In another aspect, the invention provides methods of making a medicalimplant containing antioxidant-doped cross-linked polymeric materialcomprising: a) machining a consolidated polymeric material, therebyforming a medical implant; b) irradiating the medical implant, therebyforming a medical implant containing cross-linked polymeric material;and c) doping the medical implant with an antioxidant by diffusion.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) directcompression molding polymeric material, thereby forming a medicalimplant; b) doping the medical implant with an antioxidant by diffusion;c) packaging the medical implant; and d) irradiating the packagedmedical implant by ionizing radiation, thereby forming a consolidatedand cross-linked and sterile medical implant.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a)machining a consolidated polymeric material, thereby forming a medicalimplant; b) doping the medical implant with an antioxidant by diffusion;c) packaging the medical implant; and d) irradiating the packagedmedical implant by ionizing radiation, thereby forming a consolidatedand cross-linked and sterile medical implant.

In another aspect, the invention provides methods of making cross-linkedpolymeric material comprising the steps of: a) placing a consolidatedand cross-linked polymeric material in a pressure chamber; b) fillingthe chamber with an antioxidant; and c) pressurizing the chamber toenhance diffusion of the antioxidant into the consolidated andcross-linked polymeric material.

In another aspect, the invention provides methods of making medicaldevices containing cross-linked polymeric material comprising: a)irradiating a manufactured medical device consisting of consolidatedpolymeric material with ionizing radiation, thereby forming aconsolidated and cross-linked polymeric material; and b) doping theconsolidated and cross-linked polymeric material with an antioxidant bydiffusion, thereby forming an antioxidant-doped consolidated andcross-linked polymeric material.

In another aspect, the invention provides methods of making a packagingfor medical devices that is resistant to oxidation, when subjected toeither sterilization or crosslinking doses of ionizing radiation,comprising: a) doping the packaging material with an antioxidant bydiffusion; b) inserting a medical device in the packaging material; c)sealing the packaging material containing the medical device, therebyforming a packaged medical device; and d) irradiating the packagedmedical device with ionizing radiation or gas sterilization.

In another aspect, the invention provides methods of making a packagingfor pharmaceutical compounds that is resistant to oxidation, whensubjected to either sterilization or crosslinking doses of ionizingradiation, comprising: a) doping the packaging material with anantioxidant by diffusion; b) inserting a pharmaceutical compound in thepackaging material; c) sealing the packaging material containing thepharmaceutical compound, thereby forming a packaged pharmaceuticalcompound; and d) irradiating the packaged pharmaceutical compound withionizing radiation or gas sterilization.

Yet in another aspect, the invention provides methods of making amedical implant containing cross-linked polymeric material, wherein theimplant comprises medical devices, including acetabular liner, shoulderglenoid, patellar component, finger joint component, ankle jointcomponent, elbow joint component, wrist joint component, toe jointcomponent, bipolar hip replacements, tibial knee insert, tibial kneeinserts with reinforcing metallic and polyethylene posts, intervertebraldiscs, heart valves, tendons, stents, and vascular grafts, wherein thepolymeric material is polymeric resin powder, polymeric flakes,polymeric particles, or the like, or a mixture thereof.

Yet in another aspect, the invention provides methods of making medicalimplants, including non-permanent implants, containing cross-linkedpolymeric material, wherein the implant comprises medical device,including balloon catheters, sutures, tubing, and intravenous tubing,wherein the polymeric material is polymeric resin powder, polymericflakes, polymeric particles, or the like, or a mixture thereof. Asdescribed herein, the polymeric balloons, for example, polyether-blockco-polyamide polymer (PeBAX®), Nylon, and polyethylene terephthalate(PET) balloons are doped with vitamin E and irradiated before, during,or after doping.

Yet in another aspect, the invention provides methods of making apackaging for a medical device, wherein the packaging is resistant tooxidation when subjected to sterilization with ionizing radiation or gassterilization. The packaging include barrier materials, for example,blow-molded blister packs, heat-shrinkable packaging, thermally-sealedpackaging, or the like or a mixture thereof.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) dopingthe consolidated polymeric material with an antioxidant by diffusion;and b) irradiating the polymeric material with ionizing radiation,thereby forming a consolidated and cross-linked polymeric material.

In one aspect, antioxidant-doped medical implants are packaged andsterilized by ionizing radiation or gas sterilization to obtain sterileand cross-linked medical implants.

In another aspect, the polymeric material of the instant invention is apolymeric resin powder, polymeric flakes, polymeric particles, or thelike, or a mixture thereof, wherein the irradiation can be carried outin an atmosphere containing between about 1% and about 22% oxygen,wherein the radiation dose is between about 25 kGy and about 1000 kGy.

In another aspect, the polymeric material of the instant invention ispolymeric resin powder, polymeric flakes, polymeric particles, or thelike, or a mixture thereof, wherein the polymeric material is irradiatedafter consolidation in an inert atmosphere containing a gas, forexample, nitrogen, argon, helium, neon, or the like, or a combinationthereof, wherein the radiation dose is between about 25 kGy and about1000 kGy.

In another aspect, the polymeric material of the instant invention isconsolidated polymeric material, where the consolidation can be carriedout by compression molding to form a slab from which a medical device ismachined.

In another aspect, the polymeric material of the instant invention isconsolidated polymeric material, where the consolidation can be carriedout by direct compression molding to form a finished medical device.

Yet in another aspect, the polymeric material of the instant inventionis consolidated polymeric material, where the consolidation can becarried out by compression molding to another piece to form an interfaceand an interlocked hybrid material.

Still in another aspect, the invention provides methods of making amedical implant containing cross-linked polymeric material comprising:a) compression molding of polymeric material to another piece, therebyforming an interface and an interlocked hybrid material; b) irradiatingthe interlocked hybrid material by ionizing radiation, thereby forming across-linked and interlocked hybrid material; and c) doping thecross-linked and interlocked hybrid material with an antioxidant bydiffusion.

According to one aspect, the invention provides methods of making amedical implant containing cross-linked polymeric material comprisingcompression molding of polymeric material to another piece, such as ametallic or a non metallic piece, for example, a metal, a ceramic, or apolymer, thereby forming an interface and an interlocked hybridmaterial, wherein the interface is a metal-polymer or a metal-ceramicinterface.

Yet according to another aspect, the invention provides methods ofmaking a medical implant containing cross-linked polymeric materialcomprising: a) compression molding of polymeric material to anotherpiece, thereby forming an interface and an interlocked hybrid material;b) doping the interlocked hybrid material with an antioxidant, forexample, an α-tocopherol, such as vitamin E, by diffusion; and c)irradiating the interlocked hybrid material by ionizing radiation,thereby forming a cross-linked and interlocked hybrid material.

Another aspect of the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a)compression molding a polymeric material, thereby forming a medicalimplant; b) irradiating the medical implant to crosslink the polymericmaterial; c) doping the irradiated medical implant with an antioxidantby diffusion; d) packaging the irradiated and antioxidant-doped medicalimplant; and e) sterilizing the packaged irradiated andantioxidant-doped medical implant by ionizing radiation or gassterilization, thereby forming a cross-linked and sterile medicalimplant.

Yet in another aspect, the invention provides methods of making amedical implant containing cross-linked polymeric material comprising:a) machining a consolidated polymeric material, thereby forming amedical implant; b) irradiating the medical implant to crosslink thepolymeric material; c) doping the irradiated medical implant with anantioxidant by diffusion; d) packaging the irradiated andantioxidant-doped medical implant; and e) sterilizing the packagedirradiated and antioxidant-doped medical implant by ionizing radiationor gas sterilization, thereby forming a cross-linked and sterile medicalimplant.

According to another aspect, the invention provides methods of making amedical implant containing cross-linked polymeric material comprising:a) compression molding of polymeric material to another piece, therebyforming an interface and an interlocked hybrid material; b) doping theinterlocked hybrid material with an antioxidant by diffusion; and c)irradiating the interlocked hybrid material by ionizing radiation,thereby forming a cross-linked and interlocked hybrid material.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) directcompression molding of the polymeric material, thereby forming a medicalimplant; b) irradiating the medical implant by ionizing radiation,thereby forming a consolidated and cross-linked medical implant; and c)doping the consolidated and cross-linked medical implant with anantioxidant by diffusion.

Yet in another aspect, the invention provides methods of making amedical implant containing cross-linked polymeric material comprising:a) machining a consolidated polymeric material, thereby forming amedical implant; b) irradiating the medical implant by ionizingradiation, thereby forming a consolidated and cross-linked medicalimplant; and c) doping the consolidated and cross-linked medical implantan antioxidant by diffusion.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) doping the consolidated polymeric materialwith an antioxidant by diffusion; d) irradiating the antioxidant dopedpolymeric material by ionizing radiation, thereby forming an antioxidantdoped cross-linked polymeric material; and e) machining the cross-linkedpolymeric material, thereby forming an antioxidant doped cross-linkedmedical implant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a consolidated polymeric material; b)doping the consolidated polymeric material with an antioxidant bydiffusion; c) irradiating the antioxidant doped polymeric material byionizing radiation, thereby forming an antioxidant doped cross-linkedpolymeric material; and d) machining the cross-linked polymericmaterial, thereby forming an antioxidant doped cross-linked medicalimplant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) doping the consolidated polymeric materialwith an antioxidant by diffusion; d) machining the antioxidant dopedpolymeric material, thereby forming an antioxidant doped polymericmaterial; and e) irradiating the antioxidant doped cross-linkedpolymeric material by ionizing radiation, thereby forming an antioxidantdoped cross-linked medical implant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a consolidated polymeric material; b)doping the consolidated polymeric material with an antioxidant bydiffusion; c) machining the antioxidant doped polymeric material,thereby forming an antioxidant doped polymeric material; and d)irradiating the antioxidant doped cross-linked polymeric material byionizing radiation, thereby forming an antioxidant doped cross-linkedmedical implant.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) directcompression molding polymeric material, thereby forming a medicalimplant; b) doping the medical implant an antioxidant by diffusion; c)packaging the medical implant; and d) irradiating the packaged medicalimplant by ionizing radiation, thereby forming a consolidated andcross-linked and sterile medical implant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) machining the consolidated polymericmaterial, thereby forming a medical implant; d) doping the medicalimplant with an antioxidant by diffusion, thereby forming an antioxidantdoped medical implant; e) packaging the medical implant; and f)irradiating the packaged medical implant by ionizing radiation, therebyforming an antioxidant doped cross-linked and sterile medical implant.

Yet in another aspect, the invention provides methods of making amedical implant comprising: a) providing a consolidated polymericmaterial; b) machining the consolidated polymeric material, therebyforming a medical implant; c) doping the medical implant with anantioxidant by diffusion, thereby forming an antioxidant doped medicalimplant; d) packaging the medical implant; and e) irradiating thepackaged medical implant by ionizing radiation, thereby forming anantioxidant doped cross-linked and sterile medical implant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) doping the consolidated polymeric materialwith an antioxidant by diffusion, thereby forming an antioxidant dopedpolymeric material; d) machining the antioxidant-doped polymericmaterial, thereby forming a medical implant; e) packaging the medicalimplant; and f) irradiating the packaged medical implant by ionizingradiation, thereby forming an antioxidant doped cross-linked and sterilemedical implant.

Yet in another aspect, the invention provides methods of making amedical implant comprising: a) providing a consolidated polymericmaterial; b) doping the consolidated polymeric material with anantioxidant by diffusion, thereby forming an antioxidant doped polymericmaterial; c) machining the antioxidant-doped polymeric material, therebyforming a medical implant; d) packaging the medical implant; and e)irradiating the packaged medical implant by ionizing radiation, therebyforming an antioxidant doped cross-linked and sterile medical implant.

In another aspect, the invention provides methods of making a sterilemedical implant containing antioxidant doped cross-linked polymericmaterial comprising: a) irradiating a consolidated polymeric material,thereby forming a cross-linked polymeric material; b) machining theconsolidated and cross-linked polymeric material, thereby forming amedical implant; c) doping the medical implant with an antioxidant bydiffusion; d) packaging the irradiated and antioxidant-doped medicalimplant; and e) sterilizing the packaged medical implant by ionizingradiation or gas sterilization, thereby forming a cross-linked andsterile medical implant.

In another aspect, the invention provides methods of making a sterilemedical implant containing antioxidant doped cross-linked polymericmaterial comprising: a) doping a polymeric material with an antioxidant;b) consolidating the antioxidant-doped polymeric material; c) machiningthe consolidated antioxidant-doped polymeric material, thereby formingan antioxidant-doped medical implant; d) irradiating the medicalimplant, thereby forming a medical implant containing antioxidant-dopedcross-linked polymeric material; e) packaging the antioxidant-dopedcross-linked medical implant; and f) sterilizing the packaged medicalimplant by ionizing radiation or gas sterilization, thereby forming across-linked and sterile medical implant.

In another aspect, the invention provides methods of making a sterilemedical implant containing antioxidant doped cross-linked polymericmaterial comprising: a) doping a polymeric material with an antioxidant;b) consolidating the antioxidant-doped polymeric material; c)irradiating the consolidated polymeric material, thereby forming anantioxidant-doped cross-linked polymeric material; d) machining theconsolidated and cross-linked polymeric material, thereby forming amedical implant containing an antioxidant-doped cross-linked polymericmaterial; e) packaging the antioxidant-doped cross-linked medicalimplant; and f) sterilizing the packaged medical implant by ionizingradiation or gas sterilization, thereby forming a cross-linked andsterile medical implant.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a) dopinga polymeric material with an antioxidant by diffusion; b) irradiatingthe antioxidant-doped polymeric material by ionizing radiation, therebyforming a cross-linked antioxidant-doped polymeric material; and c)compression molding of the cross-linked antioxidant-doped polymericmaterial to another piece, thereby forming a cross-linked andinterlocked hybrid material.

In another aspect, the invention provides methods of making a medicalimplant containing cross-linked polymeric material comprising: a)irradiating a consolidated polymeric material by ionizing radiation,thereby forming a consolidated and cross-linked polymeric material; b)direct compression molding of the polymeric material, thereby forming aconsolidated and cross-linked medical implant; and c) doping theconsolidated and cross-linked medical implant with an antioxidant bydiffusion.

In another aspect, the invention provides methods of making a medicalimplant containing antioxidant doped cross-linked polymeric materialcomprising: a) doping a polymeric material with an antioxidant; b)consolidating the antioxidant-doped polymeric material; c) machining theconsolidated antioxidant-doped polymeric material, thereby forming anantioxidant-doped medical implant; and d) irradiating the medicalimplant, thereby forming a medical implant containing antioxidant-dopedcross-linked polymeric material.

In another aspect, the invention provides methods of making a medicalimplant containing antioxidant doped cross-linked polymeric materialcomprising: a) doping a polymeric material with an antioxidant; b)consolidating the antioxidant-doped polymeric material; c) irradiatingthe consolidated polymeric material, thereby forming anantioxidant-doped cross-linked polymeric material; and d) machining theconsolidated and cross-linked polymeric material, thereby forming amedical implant containing an antioxidant-doped cross-linked polymericmaterial.

Yet in another aspect, the invention provides methods of making anon-permanent medical device containing cross-linked polymeric materialcomprising: a) doping a manufactured medical device containingconsolidated polymeric material with an antioxidant by diffusion,thereby forming an antioxidant-doped polymeric material; and b)irradiating the medical device with ionizing radiation, thereby forminga cross-linked polymeric material.

In another aspect, the invention provides non-oxidizing cross-linkedpolymeric materials with detectable residual free radicals.

In another aspect, the invention provides non-oxidizing cross-linkedmedical implants, including permanent and non-permanent medical devices,with detectable residual free radicals.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) machining the consolidated polymericmaterial, thereby forming a medical implant; d) irradiating the medicalimplant with ionizing radiation, thereby forming a cross-linked medicalimplant; and e) doping the medical implant with an antioxidant bydiffusion, thereby forming an antioxidant-doped cross-linked medicalimplant.

Yet in another aspect, the invention provides methods of making amedical implant comprising: a) providing a consolidated polymericmaterial; b) machining the consolidated polymeric material, therebyforming a medical implant; c) irradiating the medical implant withionizing radiation, thereby forming an antioxidant-doped cross-linkedmedical implant; and d) doping the medical implant with an antioxidantby diffusion, thereby forming an antioxidant-doped cross-linked medicalimplant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) machining the consolidated polymericmaterial, thereby forming a medical implant; d) doping the medicalimplant with an antioxidant by diffusion, thereby forming anantioxidant-doped medical implant; and e) irradiating the medicalimplant with ionizing radiation, thereby forming an antioxidant-dopedcross-linked medical implant.

Yet in another aspect, the invention provides methods of making amedical implant comprising: a) providing a consolidated polymericmaterial; b) machining the consolidated polymeric material, therebyforming a medical implant; c) doping the medical implant with anantioxidant by diffusion, thereby forming an antioxidant-doped medicalimplant; and d) irradiating the medical implant with ionizing radiation,thereby forming an antioxidant-doped cross-linked medical implant.

In another aspect, the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) consolidatingthe polymeric material; c) irradiating the polymeric material withionizing radiation, thereby forming a cross-linked polymeric material;d) doping the polymeric material with an antioxidant by diffusion,thereby forming an antioxidant-doped cross-linked polymeric material;and e) machining the polymeric material, thereby forming anantioxidant-doped cross-linked medical implant.

Yet in another aspect, the invention provides methods of making amedical implant comprising: a) providing a consolidated polymericmaterial; b) irradiating the polymeric material with ionizing radiation,thereby forming a cross-linked polymeric material; c) doping thepolymeric material with an antioxidant by diffusion, thereby forming anantioxidant-doped cross-linked polymeric material; and d) machining thepolymeric material, thereby forming an antioxidant-doped cross-linkedmedical implant.

Another aspect of the invention provides methods of making a medicalimplant comprising: a) providing a polymeric material; b) compressionmolding the polymeric material, thereby forming a medical implant; c)doping the medical implant containing an interface or an interlockedhybrid material with an antioxidant by diffusion, thereby forming anantioxidant-doped medical implant; d) packaging the medical implant; ande) irradiating the packaged medical implant by ionizing radiation,thereby forming an antioxidant-doped cross-linked and sterile medicalimplant. In another aspect, the polymeric material is compression moldedto another piece or a medical implant, thereby form an interface or aninterlocked hybrid material.

Another aspect of the invention provides methods of making a medicalimplant comprising: a) providing a compression molded polymeric materialforming a medical implant; b) doping the medical implant containing aninterface or an interlocked hybrid material with an antioxidant bydiffusion, thereby forming an antioxidant-doped medical implant; c)packaging the medical implant; and d) irradiating the packaged medicalimplant by ionizing radiation, thereby forming an antioxidant-dopedcross-linked and sterile medical implant. In another aspect, thepolymeric material is compression molded to another piece or a medicalimplant, thereby form an interface or an interlocked hybrid material.

Another aspect of the invention provides methods to increase theuniformity of an antioxidant in a doped polymeric material by annealingthe doped polymeric material below the melting point of the dopedpolymeric material.

Another aspect of the invention provides methods to increase theuniformity of an antioxidant in a doped polymeric material by annealingthe doped polymeric material above the melting point of the dopedpolymeric material.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows penetration depth of vitamin E diffusion into UHMWPE atroom temperature, 100° C., 120° C. and 130° C.

FIG. 2 shows the oxidation index profile as a function of depth into oneof the representative aged cubes of seven groups studied (Group TCRT,Group RT1, Group RT16, Group TC100C16, Group 100C1, Group TC100C1, andGroup 100C16). All cubes were fabricated from an irradiated polyethyleneand four of which were doped with vitamin E under various conditions.Thermal control cubes were not treated with vitamin E. Vitamin E dopedcubes show less oxidation at the surface and in the bulk of the samplesthan their corresponding thermal controls.

FIG. 3 shows the diffusion profiles for vitamin E through unirradiatedUHMWPE doped at 130° C. for 96 hours as a function of subsequentannealing time at 130° C.

FIG. 4 schematically shows examples of sequences of processing UHMWPEand doping at various steps.

FIGS. 5A and 5B schematically shows examples of sequences of processingUHMWPE and doping at various steps.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides methods of making oxidation resistantmedical implants that comprise medical devices, including permanent andnon-permanent devices, and packaging that comprises polymeric material,such as polyethylene. The invention pertains to methods of dopingconsolidated polyethylene, such as UHMWPE, with antioxidants, before,during, or after crosslinking the consolidated polyethylene.

In one aspect of the invention, the doping of consolidated polyethylenecan be carried out by diffusion of an antioxidant, for example,α-tocopherol, such as vitamin E. According to one aspect of theinvention, the diffusion of the antioxidant is accelerated by increasingthe temperature and/or pressure.

According to another aspect of the invention, an antioxidant isdelivered in various forms, including in a pure form, for example, aspure vitamin E, or dissolved in a solvent.

According to another aspect of the invention, diffusion rate of anantioxidant into the polyethylene is increased by increasing theconcentration of the antioxidant solution, for example, a vitamin Esolution.

In accordance with another aspect of the invention, diffusion rate of anantioxidant into the polyethylene is increased by swelling theconsolidated polyethylene in a supercritical fluid, for example, in asupercritical CO₂, i.e., the temperature being above the supercriticaltemperature, which is 31.3° C., and the pressure being above thesupercritical pressure, which is 73.8 bar.

In general, for example, in case of vitamin E, as the antioxidant,mixing the resin powder, flakes, particles, or a mixture thereof, withvitamin E and consolidation thereafter result in changes in color ofpolymeric material to yellow. According to the instant invention, dopingsubsequent to consolidation avoids the exposure of vitamin E to hightemperatures and pressures of consolidation and prevents thediscoloration of the polymeric material. The invention also decreasesthe thermal effects on the antioxidant. The thermal effects can reducethe effectiveness of the antioxidant in protecting the polymericmaterial against oxidation.

Doping in the consolidated state also allows one to achieve a gradientof antioxidant in consolidated polymeric material. One can dope acertain thickness surface layer where the oxidation of the polymericmaterial in a medical device is of concern in terms of wear. This can beachieved by simply dipping or soaking finished devices, for example, afinished medical implant, for example, in pure vitamin E or in asolution of vitamin E at a given temperature and for a given amount oftime.

According to the methods described herein, an antioxidant, for example,vitamin E, can be doped into the polymeric material either before,during, or after irradiation (See for example, FIGS. 4 and 5).

It may be possible that the doped antioxidant can leach out of thepolymeric material used in fabrication of medical implants or medicaldevices either during storage prior to use or during in vivo service.For a permanent medical device, the in vivo duration can be as long asthe remaining life of the patient, which is the length of time betweenimplantation of the device and the death of the patient, for example,1-120 years. If leaching out of the antioxidant is an issue, theirradiation of the medical implant or medical device or irradiation ofany portion thereof can be carried out after doping the antioxidant.This can ensure crosslinking of the antioxidant to the host polymerthrough covalent bonds and thereby prevent loss of antioxidant from themedical implant or the device.

According to another aspect of the invention, polymeric material, forexample, resin powder, flakes, particles, or a mixture thereof, is mixedwith an antioxidant and then the mixture is consolidated. Theconsolidated antioxidant doped polymeric material can be machined to useas a component in a medical implant or as a medical device.

According to another aspect of the invention, consolidated polymericmaterial, for example, consolidated resin powder, molded sheet, blownfilms, tubes, balloons, flakes, particles, or a mixture thereof, can bedoped with an antioxidant, for example, vitamin E in the form ofα-Tocopherol, by diffusion. Consolidated polymeric material, forexample, consolidated UHMWPE can be soaked in 100% vitamin E or in asolution of α-Tocopherol in an alcohol, for example, ethanol orisopropanol. A solution of α-Tocopherol, about 50% by weight in ethanolcan be used to diffuse in to UHMWPE in contact with a supercriticalfluid, such as CO₂. The balloons, for example, PeBAX®, Nylon, and PETballoons can be doped with vitamin E and irradiated before, during, orafter doping.

The invention also relates to the following processing steps tofabricate medical devices made out of highly cross-linked polyethyleneand containing metallic pieces such as bipolar hip replacements, tibialknee inserts with reinforcing metallic and polyethylene posts,intervertebral disc systems, and for any implant that contains a surfacethat cannot be readily sterilized by a gas sterilization method.

According to one aspect of the invention, the polyethylene component ofa medical implant is in close contact with another material, such as ametallic mesh or back, a non-metallic mesh or back, a tibial tray, apatella tray, or an acetabular shell, wherein the polyethylene, such asresin powder, flakes and particles are directly compression molded tothese counter faces. For example, a polyethylene tibial insert ismanufactured by compression molding of polyethylene resin powder to atibial tray, to a metallic mesh or back or to a non-metallic mesh orback. In the latter case, the mesh is shaped to serve as a fixationinterface with the bone, through either bony in-growth or the use of anadhesive, such as polymethylmethacrylate (PMMA) bone cement. Theseshapes are of various forms including, acetabular liner, tibial tray fortotal or unicompartmental knee implants, patella tray, and glenoidcomponent, ankle, elbow or finger component. Another aspect of theinvention relates to mechanical interlocking of the molded polyethylenewith the other piece(s), for example, a metallic or a non-metallicpiece, that makes up part of the implant.

The interface geometry is crucial in that polyethylene assumes thegeometry as its consolidated shape. Polyethylene has a remarkableproperty of ‘shape memory’ due to its very high molecular weight thatresults in a high density of physical entanglements. Followingconsolidation, plastic deformation introduces a permanent shape change,which attains a preferred high entropy shape when melted. This recoveryof the original consolidated shape is due to the ‘shape memory’, whichis achieved when the polyethylene is consolidated.

The recovery of polymeric material when subjected to annealing in aneffort to quench residual free radicals is also problematic in medicaldevices that have a high degree of orientation. Balloon catheters oftencan have intended axial and radial alignment of the polymeric chains.Balloon catheters made from polyethylene benefit from the improved wearresistance generated from crosslinking when used with stents.Additionally, the use of catheters and stents coated with drugsprecludes the use of ethylene oxide sterilization in some cases; thusionizing radiation must be used, and the balloon catheter has to beprotected from the deleterious effects of free-radical inducedoxidation. Annealing of these materials close to the melt transitiontemperature would result in bulk chain motion and subsequent loss ofdimensional tolerances of the part. By diffusing 100% vitamin E or in asolution of α-Tocopherol in an alcohol, for example, ethanol orisopropanol, into the medical device, such as a balloon catheter, eitherbefore, during, or after exposure to ionizing radiation for eithercrosslinking or sterilization, the problems associated withpost-irradiation oxidation can be avoided without the need for thermaltreatment. As described herein, the balloons, for example, PeBAX®,Nylon, and PET balloons can be doped with vitamin E and irradiatedbefore, during, or after doping.

Another aspect of the invention provides that following the compressionmoldings of the polyethylene to the counterface with the mechanicalinterlock, the hybrid component is irradiated using ionizing radiationto a desired dose level, for example, about 25 kGy to about 1000 kGy,preferably between about 25 kGy and about 150 kGy, more preferablybetween about 50 kGy and about 100 kGy. Another aspect of the inventiondiscloses that the irradiation step generates residual free radicals andtherefore, a melting step is introduced thereafter to quench theresidual free radicals. Since the polyethylene is consolidated into theshape of the interface, thereby setting a ‘shape memory’ of the polymer,the polyethylene does not separate from the counterface.

In another aspect of the invention, there are provided methods ofcrosslinking polyethylene, to create a polyethylene-based medicaldevice, wherein the device is immersed in a non-oxidizing medium such asinert gas or inert fluid, wherein the medium is heated to above themelting point of the irradiated polyethylene, for example, UHMWPE (aboveabout 137° C.) to eliminate the crystalline matter and to allow therecombination/elimination of the residual free radicals. Because theshape memory of the compression molded polymer is set at themechanically interlocked interface and that memory is strengthened bythe crosslinking step, there is no significant separation at theinterface between the polyethylene and the counterface.

Another aspect of the invention provides that following the above stepsof free radical elimination, the interface between the metal and thepolymer become sterile due to the high irradiation dose level usedduring irradiation. When there is substantial oxidation on the outsidesurface of the polyethylene induced during the free radical eliminationstep or irradiation step, the device surface can be further machined toremove the oxidized surface layer. In another aspect, the inventionprovides that in the case of a post-melting machining of an implant, themelting step can be carried out in the presence of an inert gas.

Another aspect of the invention includes methods of sterilization of thefabricated device, wherein the device is further sterilized withethylene oxide, gas plasma, or the other gases, when the interface issterile but the rest of the component is not.

In another aspect, the invention discloses packaging of irradiated andantioxidant-doped medical implants or medical devices includingcompression molded implants or devices, wherein the implants or thedevices can be sterilized by ionizing radiation or gas sterilization toobtain sterile and cross-linked medical implants or medical devices.

DEFINITIONS

“Antioxidant” refers to what is known in the art as (see, for example,WO 01/80778, U.S. Pat. No. 6,448,315). Alpha- and delta-tocopherol;propyl, octyl, or dedocyl gallates; lactic, citric, and tartaric acidsand their salts; orthophosphates, tocopherol acetate. Preferably vitaminE.

“Supercritical fluid” refers to what is known in the art, for example,supercritical propane, acetylene, carbon dioxide (CO₂). In thisconnection the critical temperature is that temperature above which agas cannot be liquefied by pressure alone. The pressure under which asubstance may exist as a gas in equilibrium with the liquid at thecritical temperature is the critical pressure. Supercritical fluidcondition generally means that the fluid is subjected to such atemperature and such a pressure that a supercritical fluid and thereby asupercritical fluid mixture is obtained, the temperature being above thesupercritical temperature, which for CO₂ is 31.3° C., and the pressurebeing above the supercritical pressure, which for CO₂ is 73.8 bar. Morespecifically, supercritical condition refers to a condition of amixture, for example, UHMWPE with an antioxidant, at an elevatedtemperature and pressure, when a supercritical fluid mixture is formedand then evaporate CO₂ from the mixture, UHMWPE doped with anantioxidant is obtained (see, for example, U.S. Pat. No. 6,448,315 andWO 02/26464)

The term “compression molding” as referred herein related generally towhat is known in the art and specifically relates to high temperaturemolding polymeric material wherein polymeric material is in any physicalstate, including powder form, is compressed into a slab form or mold ofa medical implant, for example, a tibial insert, an acetabular liner, aglenoid liner, a patella, or an unicompartmental insert, can bemachined.

The term “direct compression molding” as referred herein relatedgenerally to what is known in the art and specifically relates tomolding applicable in polyethylene-based devices, for example, medicalimplants wherein polyethylene in any physical state, including powderform, is compressed to solid support, for example, a metallic back,metallic mesh, or metal surface containing grooves, undercuts, orcutouts. The compression molding also includes high temperaturecompression molding of polyethylene at various states, including resinpowder, flakes and particles, to make a component of a medical implant,for example, a tibial insert, an acetabular liner, a glenoid liner, apatella, or an unicompartmental insert.

The term “mechanically interlocked” refers generally to interlocking ofpolyethylene and the counterface, that are produced by various methods,including compression molding, heat and irradiation, thereby forming aninterlocking interface, resulting into a ‘shape memory’ of theinterlocked polyethylene. Components of a device having such aninterlocking interface can be referred to as a “hybrid material”.Medical implants having such a hybrid material, contain a substantiallysterile interface.

The term “substantially sterile” refers to a condition of an object, forexample, an interface or a hybrid material or a medical implantcontaining interface(s), wherein the interface is sufficiently sterileto be medically acceptable, i.e., will not cause an infection or requirerevision surgery.

“Metallic mesh” refers to a porous metallic surface of various poresizes, for example, 0.1-3 mm. The porous surface can be obtained throughseveral different methods, for example, sintering of metallic powderwith a binder that is subsequently removed to leave behind a poroussurface; sintering of short metallic fibers of diameter 0.1-3 mm; orsintering of different size metallic meshes on top of each other toprovide an open continuous pore structure.

“Bone cement” refers to what is known in the art as an adhesive used inbonding medical devices to bone. Typically, bone cement is made out ofpolymethylmethacrylate (PMMA).

“High temperature compression molding” refers to the compression moldingof polyethylene in any form, for example, resin powder, flakes orparticles, to impart new geometry under pressure and temperature. Duringthe high temperature (above the melting point of polyethylene)compression molding, polyethylene is heated to above its melting point,pressurized into a mold of desired shape and allowed to cool down underpressure to maintain a desired shape.

“Shape memory” refers to what is known in the art as the property ofpolyethylene, for example, an UHMWPE, that attains a preferred highentropy shape when melted. The preferred high entropy shape is achievedwhen the resin powder is is consolidated through compression molding.

The phrase “substantially no detectable residual free radicals” refersto a state of a polyethylene component, wherein enough free radicals areeliminated to avoid oxidative degradation, which can be evaluated byelectron spin resonance (ESR). The phrase “detectable residual freeradicals” refers to the lowest level of free radicals detectable by ESRor more. The lowest level of free radicals detectable withstate-of-the-art instruments is about 10¹⁴ spins/gram and thus the term“detectable” refers to a detection limit of 10¹⁴ spins/gram by ESR.

The terms “about” or “approximately” in the context of numerical valuesand ranges refers to values or ranges that approximate or are close tothe recited values or ranges such that the invention can perform asintended, such as having a desired degree of crosslinking and/or adesired lack of free radicals, as is apparent to the skilled person fromthe teachings contained herein. This is due, at least in part, to thevarying properties of polymer compositions. Thus these terms encompassvalues beyond those resulting from systematic error.

Polymeric Material: Ultra-high molecular weight polyethylene (UHMWPE)refers to linear non-branched chains of ethylene having molecularweights in excess of about 500,000, preferably above about 1,000,000,and more preferably above about 2,000,000. Often the molecular weightscan reach about 8,000,000 or more. By initial average molecular weightis meant the average molecular weight of the UHMWPE starting material,prior to any irradiation. See U.S. Pat. No. 5,879,400, PCT/US99/16070,filed on Jul. 16, 1999, and PCT/US97/02220, filed Feb. 11, 1997.

The products and processes of this invention also apply to various typesof polymeric materials, for example, any polyolefin, includinghigh-density-polyethylene, low-density-polyethylene,linear-low-density-polyethylene, ultra-high molecular weightpolyethylene (UHMWPE), or mixtures thereof. Polymeric materials, as usedherein, also applies to polyethylene of various forms, for example,resin powder, flakes, particles, powder, or a mixture thereof, or aconsolidated form derived from any of the above.

Crosslinking Polymeric Material: Polymeric Materials, for example,UHMWPE can be cross-linked by a variety of approaches, including thoseemploying cross-linking chemicals (such as peroxides and/or silane)and/or irradiation. Preferred approaches for cross-linking employirradiation. Cross-linked UHMWPE also can be obtained according to theteachings of U.S. Pat. No. 5,879,400, U.S. Pat. No. 6,641,617, andPCT/US97/02220.

Consolidated Polymeric Material: Consolidated polymeric material refersto a solid, consolidated bar stock, solid material machined from stock,or semi-solid form of polymeric material derived from any forms asdescribed herein, for example, resin powder, flakes, particles, or amixture thereof, that can be consolidated. The consolidated polymericmaterial also can be in the form of a slab, block, solid bar stock,machined component, film, tube, balloon, pre-form, implant, or finishedmedical device.

The term “non-permanent device” refers to what is known in the art as adevice that is intended for implantation in the body for a period oftime shorter than several months. Some non-permanent devices could be inthe body for a few seconds to several minutes, while other may beimplanted for days, weeks, or up to several months. Non-permanentdevices include catheters, tubing, intravenous tubing, and sutures, forexample.

“Pharmaceutical compound”, as described herein, refers to a drug in theform of a powder, suspension, emulsion, particle, film, cake, or moldedform. The drug can be free-standing or incorporated as a component of amedical device.

The term “pressure chamber” refers to a vessel or a chamber in which theinterior pressure can be raised to levels above atmospheric pressure.

The term “packaging” refers to the container or containers in which amedical device is packaged and/or shipped. Packaging can include severallevels of materials, including bags, blister packs, heat-shrinkpackaging, boxes, ampoules, bottles, tubes, trays, or the like or acombination thereof. A single component may be shipped in severalindividual types of package, for example, the component can be placed ina bag, which in turn is placed in a tray, which in turn is placed in abox. The whole assembly can be sterilized and shipped. The packagingmaterials include, but not limited to, vegetable parchments, multi-layerpolyethylene, Nylon 6, polyethylene terephthalate (PET), and polyvinylchloride-vinyl acetate copolymer films, polypropylene, polystyrene, andethylene-vinyl acetate (EVA) copolymers.

The term “sealing” refers to the process of isolating a chamber or apackage from the outside atmosphere by closing an opening in the chamberor the package. Sealing can be accomplished by a variety of means,including application of heat (for example, thermally-sealing), use ofadhesive, crimping, cold-molding, stapling, or application of pressure.

The term “blister packs” refers to a packaging comprised of a rigidplastic bowl with a lid or the like that is either peeled or puncturedto remove the packaged contents. The lid is often made of aluminum, or agas-permeable membrane such as a Tyvek. The blister packs are oftenblow-molded, a process where the plastic is heated above its deformationtemperature, at which point pressurized gas forces the plastic into therequired shape.

The term “heat-shrinkable packaging” refers to plastic films, bags, ortubes that have a high degree of orientation in them. Upon applicationof heat, the packaging shrinks down as the oriented chains retract,often wrapping tightly around the medical device.

The term “intervertebral disc system” refers to an artificial disc thatseparates the vertebrae in the spine. This system can either be composedof one type of material, or can be a composite structure, for example,cross-linked UHMWPE with metal edges.

The term “balloon catheters” refers to what is known in the art as adevice used to expand the space inside blood vessels or similar. Ballooncatheters are usually thin wall polymeric devices with an inflatabletip, and can expand blocked arteries, stents, or can be used to measureblood pressure. Commonly used polymeric balloons include, for example,polyether-block co-polyamide polymer (PeBAX®), Nylon, and polyethyleneterephthalate (PET) balloons. Commonly used polymeric material used inthe balloons and catheters include, for example, co-polymers ofpolyether and polyamide (for example, PeBAX®), Polyamides, Polyesters(for example, PET), and ethylene vinyl alcohol (EVA) used in catheterfabrication.

Medical device tubing: Materials used in medical device tubing,including an intravenous tubing include, polyvinyl chloride (PVC),polyurethane, polyolefins, and blends or alloys such as thermoplasticelastomers, polyamide/imide, polyester, polycarbonate, or variousfluoropolymers.

The term “stent” refers to what is known in the art as a metallic orpolymeric cage-like device that is used to hold bodily vessels, such asblood vessels, open. Stents are usually introduced into the body in acollapsed state, and are inflated at the desired location in the bodywith a balloon catheter, where they remain.

“Melt transition temperature” refers to the lowest temperature at whichall the crystalline domains in a material disappear.

Interface: The term “interface” in this invention is defined as theniche in medical devices formed when an implant is in a configurationwhere a component is in contact with another piece (such as a metallicor a non-metallic component), which forms an interface between thepolymer and the metal or another polymeric material. For example,interfaces of polymer-polymer or polymer-metal are in medicalprosthesis, such as orthopedic joints and bone replacement parts, forexample, hip, knee, elbow or ankle replacements.

Medical implants containing factory-assembled pieces that are in closecontact with the polyethylene form interfaces. In most cases, theinterfaces are not readily accessible to ethylene oxide gas or the gasplasma during a gas sterilization process.

Irradiation: In one aspect of the invention, the type of radiation,preferably ionizing, is used. According to another aspect of theinvention, a dose of ionizing radiation ranging from about 25 kGy toabout 1000 kGy is used. The radiation dose can be about 25 kGy, about 50kGy, about 65 kGy, about 75 kGy, about 100 kGy, about 150, kGy, about200 kGy, about 300 kGy, about 400 kGy, about 500 kGy, about 600 kGy,about 700 kGy, about 800 kGy, about 900 kGy, or about 1000 kGy, or above1000 kGy, or any integer thereabout or therebetween. Preferably, theradiation dose can be between about 25 kGy and about 150 kGy or betweenabout 50 kGy and about 100 kGy. These types of radiation, includinggamma and/or electron beam, kills or inactivates bacteria, viruses, orother microbial agents potentially contaminating medical implants,including the interfaces, thereby achieving product sterility. Theirradiation, which may be electron or gamma irradiation, in accordancewith the present invention can be carried out in air atmospherecontaining oxygen, wherein the oxygen concentration in the atmosphere isat least 1%, 2%, 4%, or up to about 22%, or any integer thereabout ortherebetween. In another aspect, the irradiation can be carried out inan inert atmosphere, wherein the atmosphere contains gas selected fromthe group consisting of nitrogen, argon, helium, neon, or the like, or acombination thereof. The irradiation also can be carried out in avacuum.

In accordance with a preferred feature of this invention, theirradiation may be carried out in a sensitizing atmosphere. This maycomprise a gaseous substance which is of sufficiently small molecularsize to diffuse into the polymer and which, on irradiation, acts as apolyfunctional grafting moiety. Examples include substituted orunsubstituted polyunsaturated hydrocarbons; for example, acetylenichydrocarbons such as acetylene; conjugated or unconjugated olefinichydrocarbons such as butadiene and (meth)acrylate monomers; sulphurmonochloride, with chloro-tri-fluoroethylene (CTFE) or acetylene beingparticularly preferred. By “gaseous” is meant herein that thesensitizing atmosphere is in the gas phase, either above or below itscritical temperature, at the irradiation temperature.

Metal Piece: In accordance with the invention, the piece forming aninterface with polymeric material is, for example, a metal. The metalpiece in functional relation with polyethylene, according to the presentinvention, can be made of a cobalt chrome alloy, stainless steel,titanium, titanium alloy or nickel cobalt alloy, for example.

Non-metallic Piece: In accordance with the invention, the piece formingan interface with polymeric material is, for example, a non-metal. Thenon-metal piece in functional relation with polyethylene, according tothe present invention, can be made of ceramic material, for example.

Inert Atmosphere: The term “inert atmosphere” refers to an environmenthaving no more than 1% oxygen and more preferably, an oxidant-freecondition that allows free radicals in polymeric materials to form crosslinks without oxidation during a process of sterilization. An inertatmosphere is used to avoid O₂, which would otherwise oxidize themedical device comprising a polymeric material, such as UHMWPE. Inertatmospheric conditions such as nitrogen, argon, helium, or neon are usedfor sterilizing polymeric medical implants by ionizing radiation.

Inert atmospheric conditions such as nitrogen, argon, helium, neon, orvacuum are also used for sterilizing interfaces of polymeric-metallicand/or polymeric-polymeric in medical implants by ionizing radiation.

Inert atmospheric conditions also refers to an inert gas, inert fluid,or inert liquid medium, such as nitrogen gas or silicon oil.

Anoxic environment: “Anoxic environment” refers to an environmentcontaining gas, such as nitrogen, with less than 21%-22% oxygen,preferably with less than 2% oxygen. The oxygen concentration in ananoxic environment also can be at least 1%, 2%, 4%, 6%, 8%, 10%, 12%14%, 16%, 18%, 20%, or up to about 22%, or any integer thereabout ortherebetween.

Vacuum: The term “vacuum” refers to an environment having no appreciableamount of gas, which otherwise would allow free radicals in polymericmaterials to form cross links without oxidation during a process ofsterilization. A vacuum is used to avoid O₂, which would otherwiseoxidize the medical device comprising a polymeric material, such asUHMWPE. A vacuum condition can be used for sterilizing polymeric medicalimplants by ionizing radiation.

A vacuum condition can be created using a commercially available vacuumpump. A vacuum condition also can be used when sterilizing interfaces ofpolymeric-metallic and/or polymeric-polymeric in medical implants byionizing radiation.

Residual Free Radicals: “Residual free radicals” refers to free radicalsthat are generated when a polymer is exposed to ionizing radiation suchas gamma or e-beam irradiation. While some of the free radicalsrecombine with each other to from crosslinks, some become trapped incrystalline domains. The trapped free radicals are also known asresidual free radicals.

According to one aspect of the invention, the levels of residual freeradicals in the polymer generated during an ionizing radiation (such asgamma or electron beam) is preferably determined using electron spinresonance and treated appropriately to reduce the free radicals.

Sterilization: One aspect of the present invention discloses a processof sterilization of medical implants containing polymeric material, suchas cross-linked UHMWPE. The process comprises sterilizing the medicalimplants by ionizing sterilization with gamma or electron beamradiation, for example, at a dose level ranging from 25-70 kGy, or bygas sterilization with ethylene oxide or gas plasma.

Another aspect of the present invention discloses a process ofsterilization of medical implants containing polymeric material, such ascross-linked UHMWPE. The process comprises sterilizing the medicalimplants by ionizing sterilization with gamma or electron beamradiation, for example, at a dose level ranging from 25-200 kGy. Thedose level of sterilization is higher than standard levels used inirradiation. This is to allow crosslinking or further crosslinking ofthe medical implants during sterilization.

In another aspect, the invention discloses a process of sterilizingmedical implants containing polymeric material, such as cross-linkedUHMWPE, that is in contact with another piece, including polymericmaterial consolidated by compression molding to another piece, therebyforming an interface and an interlocked hybrid material, comprisingsterilizing an interface by ionizing radiation; heating the medium toabove the melting point of the irradiated UHMWPE (above about 137° C.)to eliminate the crystalline matter and allow for therecombination/elimination of the residual free radicals; and sterilizingthe medical implant with a gas, for example, ethylene oxide or gasplasma.

Heating: One aspect of the present invention discloses a process ofincreasing the uniformity of the antioxidant following doping inpolymeric component of a medical implant during the manufacturingprocess by heating for a time period depending on the meltingtemperature of the polymeric material. For example, the preferredtemperature is about 137° C. or less. Another aspect of the inventiondiscloses a heating step that can be carried in the air, in anatmosphere, containing oxygen, wherein the oxygen concentration is atleast 1%, 2%, 4%, or up to about 22%, or any integer thereabout ortherebetween. In another aspect, the invention discloses a heating stepthat can be carried while the implant is in contact with an inertatmosphere, wherein the inert atmosphere contains gas selected from thegroup consisting of nitrogen, argon, helium, neon, or the like, or acombination thereof. In another aspect, the invention discloses aheating step that can be carried while the implant is in contact with anon-oxidizing medium, such as an inert fluid medium, wherein the mediumcontains no more than about 1% oxygen. In another aspect, the inventiondiscloses a heating step that can be carried while the implant is in avacuum.

In another aspect of this invention, there is described the heatingmethod of implants to reduce increase the uniformity of the antioxidant.The medical device comprising a polymeric raw material, such as UHMWPE,is generally heated to a temperature of about 137° C. or less followingthe step of doping with the antioxidant. The medical device is keptheated in the inert medium until the desired uniformity of theantioxidant is reached.

The term “below melting point” or “below the melt” refers to atemperature below the melting point of a polyethylene, for example,UHMWPE. The term “below melting point” or “below the melt” refers to atemperature less than 145° C., which may vary depending on the meltingtemperature of the polyethylene, for example, 145° C., 140° C. or 135°C., which again depends on the properties of the polyethylene beingtreated, for example, molecular weight averages and ranges, batchvariations, etc. The melting temperature is typically measured using adifferential scanning calorimeter (DSC) at a heating rate of 10° C. perminute. The peak melting temperature thus measured is referred to asmelting point and occurs, for example, at approximately 137° C. for somegrades of UHMWPE. It may be desirable to conduct a melting study on thestarting polyethylene material in order to determine the meltingtemperature and to decide upon an irradiation and annealing temperature.

The term “annealing” refers to heating the polymer below its peakmelting point. Annealing time can be at least 1 minute to several weekslong. In one aspect the annealing time is about 4 hours to about 48hours, preferably 24 to 48 hours and more preferably about 24 hours.“Annealing temperature” refers to the thermal condition for annealing inaccordance with the invention.

The term “contacted” includes physical proximity with or touching suchthat the sensitizing agent can perform its intended function.Preferably, a polyethylene composition or pre-form is sufficientlycontacted such that it is soaked in the sensitizing agent, which ensuresthat the contact is sufficient. Soaking is defined as placing the samplein a specific environment for a sufficient period of time at anappropriate temperature, for example, soaking the sample in a solutionof an antioxidant. The environment is heated to a temperature rangingfrom room temperature to a temperature below the melting point of thematerial. The contact period ranges from at least about 1 minute toseveral weeks and the duration depending on the temperature of theenvironment.

The term “non-oxidizing” refers to a state of polymeric material havingan oxidation index (A. U.) of less than about 0.5 following agingpolymeric materials for 5 weeks in air at 80° C. oven. Thus, anon-oxidizing cross-linked polymeric material generally shows anoxidation index (A. U.) of less than about 0.5 after the aging period.

Doping: Doping refers to a process well known in the art (see, forexample, U.S. Pat. Nos. 6,448,315 and 5,827,904). In this connection,doping generally refers to contacting a polymeric material with anantioxidant under certain conditions, as set forth herein, for example,doping UHMWPE with an antioxidant under supercritical conditions.

More specifically, consolidated polymeric material can be doped with anantioxidant by soaking the material in a solution of the antioxidant.This allows the antioxidant to diffuse into the polymer. For instance,the material can be soaked in 100% antioxidant. The material also can besoaked in an antioxidant solution where a carrier solvent can be used todilute the antioxidant concentration. To increase the depth of diffusionof the antioxidant, the material can be doped for longer durations, athigher temperatures, at higher pressures, and/or in presence of asupercritical fluid.

The doping process can involve soaking of a polymeric material, medicalimplant or device with an antioxidant, such as vitamin E, for about anhour up to several days, preferably for about one hour to 24 hours, morepreferably for one hour to 16 hours. The antioxidant can be heated toroom temperature or up to about 160° C. and the doping can be carriedout at room temperature or up to about 160° C. Preferably, theantioxidant can be heated to 100° C. and the doping is carried out at100° C.

The doping step can be followed by a heating step in air or in anoxicenvironment to improve the uniformity of the antioxidant within thepolymeric material, medical implant or device. The heating may becarried out above or below or at the peak melting point.

In another aspect of the invention the medical device is cleaned beforepackaging and sterilization.

The invention is further described by the following examples, which donot limit the invention in any manner.

EXAMPLES

Vitamin E: Vitamin E (Acros™ 99% D-α-Tocopherol, Fisher Brand), was usedin the experiments described herein, unless otherwise specified. Thevitamin E used is very light yellow in color and is a viscous fluid atroom temperature. Its melting point is 2-3° C.

Example 1 Consolidation of UHMWPE Resin Mixed with Vitamin E

Vitamin E was dissolved in ethanol to create a solution with 10% (w/v)vitamin E concentration. The vitamin E-ethanol solution was thendry-blended with GUR 1050 ultra-high molecular weight polyethylene(UHMWPE) resin. Two batches were prepared: one with vitamin Econcentration of 0.1% (w/v) and the other with 0.3% (w/v). The vitamin Econcentrations were measured after evaporation of ethanol. Both batcheswere than consolidated on a Carver laboratory bench pressed at atemperature of 230° C. in air. The consolidated blocks were discolored.The 0.1% (w/v) solution appeared dark yellow and the 0.3% (w/v) solutionhad a brown color. The discoloration was uniform throughout theconsolidated UHMWPE blocks.

The discoloration was thought to be the result of the degradation ofvitamin E when heated in presence of oxygen.

Example 2 Discoloration of Vitamin E when Exposed to Heat in Air or inVacuum

An experiment was carried out to determine if the vitamin Ediscoloration is due to exposure to air at elevated temperatures and ifthe discoloration could be avoided by heating vitamin E under vacuum.

One drop of vitamin E solution, as described herein, was placed on alaboratory glass slide. The glass slide was then heated in an airconvection oven to 180° C. for 1 hour in air. The vitamin E changed itscolor to a dark brown. The discoloration was most probably due to thedegradation of the vitamin E.

One drop of vitamin E was placed on a laboratory glass slide. The glassslide was then heated in a vacuum oven to 180° C. for 1 hour undervacuum. In contrast to heating in air, vitamin E showed no discerniblecolor change following heating in vacuum. Therefore, in the absence ofair or oxygen, heat treatment of vitamin E results in no discernablecolor change.

Example 3 Consolidation of UHMWPE/Vitamin E in Anoxic Environment

Vitamin E is dissolved in ethanol to create a solution. GUR1050polyethylene resin is degassed either in vacuum or is kept in an anoxicenvironment to substantially remove the dissolved oxygen. The vitaminE-ethanol solution is then dry-blended with GUR1050 polyethylene resin.Two batches are prepared, one with degassed GUR1050 and the other withthe as-received GUR1050 polyethylene resin. The dry-blended mixtures arethen separately consolidated on a Carver laboratory bench press.Consolidation can be carried out in an anoxic environment to minimizethe discoloration of the consolidated stock.

Example 4 Pin-On-Disk (POD) Wear Test of Pins Treated with 0.1% and 0.3%Vitamin E

An experiment was carried out to determine the effects of vitamin E oncrosslinking efficiency of UHMWPE. Vitamin E (α-tocopherol) was mixedwith GUR1050 UHMWPE powder, in two concentrations, for example, 0.1% and0.3% weight/volume, and consolidated. The consolidation of UHMWPE intoblocks was achieved by compression molding. One additional consolidationwas carried out without vitamin E additive, to use as a control. Thethree consolidated blocks were machined into halves and one half of eachwas packaged in vacuum and irradiated to 100 kGy with gamma radiation(Steris, Northborough, Mass.).

Cylindrical pins, 9 mm in diameter and 13 mm in length, were cut out ofthe irradiated blocks. The pins were first subjected to acceleratedaging at 80° C. for 5 weeks in air and subsequently tested on abi-directional pin-on-disk (POD). The POD test was run for a total of 2million cycles with gravimetric assessment of wear at every 0.5 millioncycles. The test was run at a frequency of 2 Hz with bovine serum, as alubricant.

The typical wear rate of UHMWPE with no radiation history and no vitaminE is around 8.0 milligram per million cycles. The wear rates for the 100kGy irradiated vitamin E added pins were 2.10±0.17 and 5.01±0.76milligram per million cycles for the 0.1% and 0.3% vitamin Econcentrations, respectively. The reduction in wear resistance is lesswith higher vitamin E content.

By increasing vitamin E content, the radiation induced long-termoxidative instability of polyethylene can be decreased. In other words,improved resistance to post-irradiation oxidation of UHMWPE can beachieved by blending with vitamin E. However, the crosslink density ofUHMWPE, achieved by a high irradiation dose, decreases with increasingconcentration of vitamin E content in the mixture.

Example 5 Diffusion of Vitamin E into Consolidated Polyethylene

A drop of vitamin E was placed on a machined surface of consolidatedGUR1050 UHMWPE in air. In six hours, the vitamin E drop was no longervisible on that machined surface, indicating that it had diffused intothe polyethylene.

Example 6 Diffusion of Vitamin E into Irradiated Polyethylene

Compression molded GUR1050 UHMWPE (Perplas, Lanchashire, UK) wasirradiated using gamma radiation at a dose level of 100 kGy. Cylindricalpins (n=10) of 9 mm diameter and 13 mm height were machined from theirradiated stock. One of the basal surfaces of five of the pins (n=5)were wetted with vitamin E. The other five pins served as controlsamples. The two groups of pins were left in air at room temperature for16 hours. They were then placed in a convection oven at 80° C. in airfor accelerated aging.

The aged pins were removed from the oven after five weeks to determinethe extent of oxidation. The pins were first cut in half along the axisof the cylinder. One of the cut surfaces was then microtomed (150-200micrometer) and a BioRad UMA 500 infra-red microscope was used tocollect infra-red spectrum as a function of distance away from the edgecorresponding to one of the basal surfaces of the cylinder. In the caseof the vitamin E treated pins, the oxidation level was quantified fromthe basal surface that was wetted with vitamin E.

Oxidation index was calculated by normalizing the area under thecarbonyl vibration (1740 cm⁻¹) to that under the methylene vibration at1370 cm⁻¹, after subtracting the corresponding baselines.

The oxidation levels were substantially reduced by the application ofvitamin E onto the surface of irradiated polyethylene. Therefore, thismethod can be used to improve the long-term oxidative stability ofirradiated polyethylene, for example, in medical devices containingpolymeric material.

Example 7 Diffusion of Vitamin E into Polyethylene Followed byIrradiation

Compression molded GUR1050 UHMWPE (Perplas, Lanchashire, UK) wasmachined into cubes (n=4) of 19 mm a side. The surfaces of two cubeswere wetted with vitamin E and left at room temperature for 16 hours.Two other cubes were left without addition of vitamin E. One cube ofeach group with and without vitamin E were packaged in an anoxicenvironment (for example, about 2% oxygen) and the remaining five cubesof each group were packaged in air. The cubes were irradiated usinggamma radiation at a dose level of 100 kGy in their respectivepackaging.

The irradiated cubes were removed from the packages and placed in anoven at 80° C. in the air for accelerated aging.

The aged cubes were removed from the oven after five weeks to determinethe extent of oxidation. The cubes were first cut into halves. One ofthe cut surfaces was then microtomed (150-200 micrometer) and a BioRadUMA 500 infra-red microscope was used to collect infra-red spectrum as afunction of distance away from one of the edges.

Oxidation index was calculated by normalizing the area under thecarbonyl vibration (1740 cm⁻¹) to that under the methylene vibration at1370 cm⁻¹, after subtracting the corresponding baselines.

The oxidation levels were substantially reduced by the application ofvitamin E onto the surface of polyethylene prior to irradiation in airor anoxic environment. Therefore, this method can be used to improve thelong-term oxidative stability of polyethylene that may subsequently beirradiated to sterilization and/or crosslinking polymeric material, forexample, medical devices containing polymeric material.

Example 8 Fabrication of a Highly Cross-Linked Medical Device

A tibial knee insert is machined from compression molded GUR1050 UHMWPE.The insert is then soaked in 100% vitamin E or a solution of vitamin E.The diffusion of vitamin E into the insert may be accelerated byincreasing temperature and/or pressure, which can be carried out eitherin air or inert or anoxic environment. After reaching desired level ofvitamin E diffusion, the insert is packaged either in air or inert oranoxic environment. The packaged insert is then irradiated to 100 kGydose. The irradiation serves two purposes: (1) crosslinks thepolyethylene and improves wear resistance and (2) sterilizes theimplant.

In this example the polyethylene implant can be any polyethylene medicaldevice including those with abutting interfaces to other materials, suchas metals. An example of this is non-modular, metal-backed, polyethylenecomponents used in total joint arthroplasty.

Example 9 Diffusion of Vitamin E in Polyethylene

An experiment was carried out to investigate the diffusion of syntheticvitamin E (DL-α-tocopherol) into UHMWPE. Consolidated GUR 1050 UHMWPE(Perplas Ltd., Lancashire, UK) was machined into 2 cm cubes. The cubeswere immersed in α-tocopherol (Fisher Scientific, Houston, Tex.) fordoping. Doping was carried out in an oven with a nitrogen purge. Cubeswere doped at 25° C., 100° C., 120° C., or 130° C. for 16 hours under0.5-0.6 atm nitrogen pressure, which was applied by first purging theoven with nitrogen, then applying vacuum, and then adjusting the amountof nitrogen (for all except 25° C., which was performed in air atambient pressure). After doping, the samples were rinsed with ethanol toremove excess α-tocopherol from surfaces of the cubes. The extent ofα-tocopherol diffusion into polyethylene was quantified by usinginfrared microscopy and measuring a characteristic absorbance ofα-tocopherol as a function of depth away from a free surface.

The cubes that were doped with α-tocopherol were machined to halves andsectioned (about 100 μm thin sections) using an LKB Sledge Microtome(Sweden). The thin sections were analyzed using a BioRad UMA 500infrared microscope (Natick, Mass.). Infrared spectra were collectedwith an aperture size of 50×50 μm as a function of depth away from oneof the edges that coincided with the free surface of the cube. Thespectra were analyzed by quantifying the absorbance, which is typicallygenerated by vitamin E, namely the absorbance between 1226 and 1275 cm⁻¹wave numbers. The area under the absorbance was integrated andnormalized to the area under the reference absorbance peak, locatedbetween 1850 and 1985 cm⁻¹. The integration of both the vitamin Eabsorbance and the reference absorbance excluded the respectivebaselines. The normalized value is referred to as vitamin E index.

FIG. 1 demonstrates the diffusion profiles of polyethylene cubes thatwere doped at four different temperatures (25° C., 100° C., 120° C. and130° C.). Depth of α-tocopherol diffusion in polyethylene increased withtemperature from 400 μm at 25° C. to 3 mm at 130° C. under ambientpressure.

The diffusion depth and uniformity of the antioxidant, in this exampleof vitamin E, can be varied by varying the doping temperature.

Example 10 Artificial Aging of UHMWPE with and without Vitamin E

An experiment was performed to investigate the effect of vitamin E onthe thermo-oxidative stability of irradiated UHMWPE. Two identicalcylindrical pins (9 mm in diameter and 13 mm in height) were machinedout of a UHMWPE block that was irradiated to 100 kGy with gammaradiation. One base of one of the cylindrical pins was coated withnatural vitamin E (DL-α-tocopherol) and the other pin was left clean.Both pins were then subjected to accelerated aging in an oven at 80° C.in air for 5 weeks. Subsequent to aging, the pins were microtomed toprepare a 200 μm thin section perpendicular to both of the cylindricalbases. Microtomed sections (200 μm each) were then analyzed with aBioRad UMA500 infra-red microscope. Infra-red spectra were collected, asa function of depth away from the edge of the microtomed section, whichcorresponded to the vitamin E exposed cylindrical base. The spectra wereanalyzed by quantifying the carbonyl absorbance between 1680 and 1780cm⁻¹ wave numbers. The area under the absorbance was integrated andnormalized to the area under the reference absorbance peak locatedbetween 1330 and 1390 cm⁻¹. The integration of both the carbonylabsorbance and the reference absorbance excluded the respectivebaselines. The normalized value is referred to as oxidation index.

The clean UHMWPE pin sample showed about six times higher oxidationindex than that of the vitamin E treated pin.

Example 11 Improved Oxidation Resistance with Vitamin E Doping

Compression molded GUR 1050 UHMWPE blocks (Perplas Ltd., Lancashire, UK)(3 inches in diameter) were gamma-irradiated in vacuum to a dose of111-kGy (Steris Isomedix, Northborough, Mass.). Irradiated blocks weremachined into half-cubes of dimensions about 2 cm×2 cm×1 cm.

Four groups of the half-cubes were soaked in α-Tocopherol (α-D,L-T,Fischer Scientific, Houston, Tex.) for doping. The half-cubes of theGroup RT1 were soaked at room temperature for one hour. The half-cubesof the Group RT16 were soaked at room temperature for 16 hour. Thehalf-cubes of the Group 100C1 were soaked at 100° C. for one hour. Thehalf-cubes of the Group 100C16 were soaked at 100° C. for 16 hours.There were a total 3 half-cubes in each group. In addition, three groupsof thermal controls were prepared with three half-cubes in each group.Group TCRT consisted of half-cubes that were machined from one of theirradiated blocks. Group TC100C1 consisted of half-cubes that wereheated to 100° C. for one hour in air. Group TC100C16 consisted ofhalf-cubes that were heated to 100° C. for 16 hours in air.

The soaked and thermal control half-cubes described above were thencleaned in a dishwasher. Cleaning was performed by a portable Kenmoredishwasher (Sears Inc, Hoffman Estates, Ill.) on normal cycle with rinseand heat drying. During cleaning, all half-cube test samples were placedin a cylindrical non-elastic polyethylene mesh of 2 inches in diameterand closed at the ends. This ensured that the samples did not movearound, but the cleaning medium could get through. Electrasol™ (ReckittBenckiser Inc., Berkshire, UK) was used as cleaning agent.

Following cleaning, the samples were subject to accelerated aging todetermine the effect of tocopherol doping under different conditions onthe oxidative stability of the irradiated UHMWPE. Accelerated aging wasperformed by placing the samples in an oven at 80° C. in air for fiveweeks.

Subsequent to aging, the half-cubes were cut in halves and microtomed toprepare a 200 μm thin section perpendicular to one of the 2 cm×2 cmsurfaces. Microtomed sections (200 μm each) were analyzed with a BioRadUMA500 infra-red microscope. Infra-red spectra were collected, as afunction of depth away from the edge of the microtomed section, whichcorresponded to the surface that was soaked in tocopherol and alsoexposed to air during aging. The spectra were analyzed by quantifyingthe carbonyl absorbance between 1680 and 1780 cm⁻¹ wave numbers. Thearea under the absorbance was integrated and normalized to the areaunder the reference absorbance peak located between 1330 and 1390 cm⁻¹.The integration of both the carbonyl absorbance and the referenceabsorbance excluded the respective baselines. The normalized value isreferred to as oxidation index.

Maximum oxidation values of each microtomed sections was calculated andaverages of three sections from each Group described above are shown inTable 1. Thermal control for 111-kGy-irradiated, cleaned and agedsamples for UHMWPE doped with tocopherol at room temperature showed highlevels of oxidation. The average maximum oxidation levels in irradiated,tocopherol doped, cleaned, and aged samples for durations of 1 hour and16 hours, respectively, were lower than their respective thermalcontrols that were not doped but had the same thermal history.

TABLE 1 Maximum oxidation values for cleaned and accelerated agedcontrol and tocopherol doped 111-kGy irradiated UHMWPE (RT denotes thatdoping was done at room temperature). Sample ID Average MaximumOxidation Index Group TCRT 3.68 ± 0.15 Group RT1 0.38 ± 0.05 Group RT160.40 ± 0.03 Group TC100C16 0.97 ± 0.04 Group 100C1 0.098 ± 0.003 GroupTC100C1 0.70 ± 0.18 Group 100C16 0.080 ± 0.003

Thermal control (Group TC100C1) for 111-kGy irradiated, cleaned and agedsamples for UHMWPE doped with tocopherol at 100° C. for 1 hour showedhigher levels of oxidation than the corresponding tocopherol doped testsamples (Group 100C1). Similarly, thermal control (Group TC100C16) for111-kGy irradiated, cleaned and aged samples for UHMWPE doped withtocopherol at 100° C. for 16 hours showed higher levels of oxidationthan the tocopherol doped test samples (Group 100C16). The oxidationlevels of the thermal controls and test samples did not show significantdifference between a soak time of 1 hour and 16 hours. The oxidationlevels for doped samples at 100° C. were less than those doped at roomtemperature.

FIG. 2 shows the oxidation index profile as a function of depth into oneof the representative aged cubes of each group studied (Group TCRT,Group RT1, Group RT16, Group TC100C16, Group 100C1, Group TC100C1, andGroup 100C16).

These results show that cleaning by washing and drying did not removethe tocopherol diffused into UHMWPE and tocopherol was able to protectagainst oxidation of high-dose irradiated UHMWPE under aggressive agingconditions.

Example 12 Ionizing Sterilization of Balloon Catheters

The increased use of drug coatings on balloons and stents precludes theuse of ethylene oxide sterilization in many cases. Additionally,improved wear behavior is desired for balloons that are used to inflatemetallic stents. Polyethylene balloons are soaked in vitamin E at roomtemperature and pressure for 16 hours. The balloons are then exposed toionizing radiation in dose levels ranging from 25 kGy to 100 kGy. Theradiation sterilizes the component without affecting the drug, andcrosslinks the polyethylene to improve the wear behavior. Oxidationresulting from residual free radicals can be minimized by the presenceof the vitamin E.

Example 13 Improved Oxidation Resistance of Packaging Material

Packaging made from polyethylene films is soaked in vitamin E at roomtemperature and kept under pressure for 16 hours. The packaging is thensterilized by ionizing radiation at doses 25-40 kGy. The packaging isprotected from oxidation-induced embrittlement, which can affect boththe mechanical integrity and the gas barrier properties of thepackaging.

Example 14 Irradiation and Doping of UHMWPE

Cubes (20 mm to a side) were machined from three different bar stocksmade out of GUR1050 UHMWPE that are treated as follows: (1) gammairradiated to 65 kGy, (2) gamma irradiated to 100 kGy, and (3)unirradiated. The cubes were than doped by soaking in vitamin E(DL-α-tocopherol) for 16 hours at room temperature. Two groups of cubes,one machined from the 65 kGy and the other from the 100 kGy irradiatedstocks, were packaged following doping with vitamin E and irradiatedagain with gamma irradiation for sterilization at a dose level of 25-40kGy. One additional group of cubes, machined from unirradiated stock,was packaged following doping with vitamin E and irradiated again withgamma irradiation for crosslinking and sterilization at a dose level of125-140 kGy.

Example 15 The Pin-On-Disk (POD) Wear Behavior of Irradiated and VitaminE Doped UHMWPE Before and after Aging

Consolidated GUR 1050 UHMWPE bar stocks were gamma irradiated at 65 kGyand 100 kGy. Cylindrical pins (9 mm in diameter and 13 mm in length)samples for POD wear testing were machined from the irradiated barstocks. The samples were doped with vitamin E (α-Tocopherol) for 16hours at room temperature in air. Following doping, the samples werefurther gamma sterilized at a dose of 27 kGy. These two groups arereferred to as α-T-92 and α-T-127 with a total radiation doses of 92 kGyand 127 kGy, respectively.

Half of the cylindrical samples were subjected to accelerated aging at80° C. in air for five weeks. Both un-aged and aged samples weresubjected to POD wear testing. The wear behavior of the pins was testedon a custom-built bi-directional pin-on-disc wear tester at a frequencyof 2 Hz by rubbing the pins against an implant-finish cobalt-chromecounterface in a rectangular wear path (Muratoglu et al., Biomaterials,20(16):1463-1470, 1999). The peak contact stress during testing was 6MPa. Bovine calf serum was used as lubricant and quantified weargravimetrically at 0.5 million-cycle intervals. Initially, the pins weresubjected to 200,000 cycles of POD testing to reach a steady state wearrate independent of diffusion or asperities on the surface. Thereafter,three pins of each group were tested for a total of 2 million cycles.The wear rate was calculated as the linear regression of wear vs. numberof cycles from 0.2 to 2 million cycles. The wear rates of doped and agedcross-linked polyethylenes are shown in Table 2.

TABLE 2 The wear rate of doped and aged cross-linked polyethylene. Wearrate Wear rate (milligrams/ (milligrams/ million-cycles) million-cycles)Sample ID before aging after aging α-T-92 (65 kGy + doping + 27 kGy) 1.5± 0.3 1.9 ± 0.5 α-T-127 (100 kGy + doping + 27 kGy) 0.82 ± 0.2  0.91 ±0.1 

The wear behavior of the doped samples were comparable before and afteraging, indicating that the presence of an antioxidant incorporated bydiffusion can protect the irradiated polyethylene from oxidation andthus prevent an increase in wear after aging. Typically the wear rate ofa 100-kGy irradiated UHMWPE is around 1 milligrams per million-cycle(Muratoglu et al., Biomaterials, 20(16):1463-1470, 1999). Aging of an105-kGy irradiated UHMWPE can increase its wear rate to above 20milligram/per cycle (Muratoglu et al. Clinical Orthopaedics & RelatedResearch, 417:253-262, 2003).

Example 16 Oxidation Stabilization of Polyether-Block Co-PolyamideBalloons

Balloons fabricated from polyether-block co-polyamide polymer (PeBAX®)are sterilized with either gamma or electron beam after packaging. Asthere is concern about oxidative embrittlement of these materials due tofree radical generation, quenching of the free radicals is imperative toensure an extended shelf life (for example, a three-year shelf life).These materials cannot be heat-treated following irradiation, given thatthe highly aligned polymer chains relax when exposed to elevatedtemperatures, resulting in radial and axial shrinkage.

Polyether-block co-polyamide balloons are soaked in vitamin E, or in asolution of vitamin E and a solvent such as an alcohol. The balloons arepackaged, and then subjected to sterilization doses ranging from 25-70kGy. The higher radiation dose results from double sterilization doses.Sterilization can occur either in air or in a low oxygen atmosphere. Thevitamin E minimizes the oxidative behavior of residual free radicalsintroduced during the sterilization process and also can reduceundesired crosslinking.

Example 17 Oxidation Stabilization of Nylon Balloons

Balloons fabricated from Nylon polymer are sterilized with either gammaor electron beam after packaging. As there is concern about oxidativeembrittlement of these materials due to free radical generation,quenching of the free radicals is imperative to ensure a three yearshelf life. These materials cannot be heat-treated followingirradiation, given that the highly aligned polymer chains relax whenexposed to elevated temperatures, resulting in radial and axialshrinkage.

Nylon balloons are soaked in vitamin E, or in a solution of vitamin Eand a solvent such as an alcohol. The balloons are packaged, and thensubjected to sterilization doses ranging from 25-70 kGy. The higherradiation dose results from double sterilization doses. Sterilizationcan occur either in air or in a low oxygen atmosphere. The vitamin Eminimizes the oxidative behavior of residual free radicals introducedduring the sterilization process and also can reduce undesiredcrosslinking.

Example 18 Oxidation Stabilization of Polyethylene TerephthalateBalloons

Balloons fabricated from polyethylene terephthalate (PET) polymer aresterilized with either gamma or electron beam after packaging. As thereis concern about oxidative embrittlement of these materials due to freeradical generation, quenching of the free radicals is imperative toensure an extended shelf life (for example, a three-year shelf life).These materials cannot be heat-treated following irradiation, given thatthe highly aligned polymer chains relax when exposed to elevatedtemperatures, resulting in radial and axial shrinkage.

PET balloons are soaked in vitamin E, or in a solution of vitamin E anda solvent such as an alcohol. The balloons are packaged, then subjectedto sterilization doses ranging from 25-70 kGy. The higher radiation doseresults from double sterilization doses. Sterilization can occur eitherin air or in a low oxygen atmosphere. The vitamin E minimizes theoxidative behavior of residual free radicals introduced during thesterilization process and also can reduce undesired crosslinking.

Example 19 Oxidation Stabilization of Multi-Component Balloons

Multi-component balloons fabricated from a combination of polymers,including polyethylene, PET, polyether-block co-polyamide, polyvinylacetate, and nylon, are sterilized with either gamma or electron beamafter packaging. As there is concern about oxidative embrittlement ofthese materials due to free radical generation, quenching of the freeradicals is imperative to ensure an extended shelf life (for example, athree-year shelf life). These materials cannot be heat-treated followingirradiation, given that the highly aligned polymer chains relax whenexposed to elevated temperatures, resulting in radial and axialshrinkage.

These multi-component balloons are soaked in vitamin E, or in a solutionof vitamin E and a solvent such as an alcohol. The balloons arepackaged, and then subjected to sterilization doses ranging from 25-70kGy. The higher radiation dose results from double sterilization doses.Sterilization can occur either in air or in a low oxygen atmosphere. Thevitamin E minimizes the oxidative behavior of residual free radicalsintroduced during the sterilization process, and also can reduceundesired crosslinking.

Example 20 Sterilization of Polypropylene Medical Devices

Polypropylene is widely used in the medical industry to producesyringes, vials, and numerous other devices, often through injectionmolding. Polypropylene is known to exhibit oxidative degradation when itis subjected to ionizing sterilization with gamma or electron beam orgas sterilization with ethylene oxide or gas plasma.

Polypropylene syringes are soaked in vitamin E, or in a solution ofvitamin E and a solvent such as an alcohol. The syringes are packaged,and then subjected to sterilization doses ranging from 25-70 kGy. Thehigher radiation dose results from double sterilization doses.Sterilization can occur either in air or in a low oxygen atmosphere. Thevitamin E will minimizes the oxidative behavior of residual freeradicals introduced during the sterilization process, and could alsoreduce undesired crosslinking.

Example 21 Sterilization of Flexible Polyvinyl Chloride Tubing

Flexible polyvinyl chloride (PVC) is used in a variety of medicaldevices, including tubing. While previously sterilized with ethyleneoxide, more manufacturers are using gamma or electron beam to sterilize.Upon exposure to ionizing radiation, these material often darken andyellow, which is believed to be due to oxidation (Medical Plastics andBiomaterials Magazine, March, 1996, Douglas W. Luther and Leonard A.Linsky). Yellowing is reduced when antioxidants are compounded into thePVC with a mechanical mixer or extruder.

PVC tubing is soaked in vitamin E, or in a solution of vitamin E and asolvent such as an alcohol. The tubing is then subjected tosterilization doses ranging from 25-70 kGy. The higher radiation doseresults from double sterilization doses. Sterilization can occur eitherin air or in a low oxygen atmosphere. The vitamin E minimizes theoxidative behavior of residual free radicals introduced during thesterilization process, and results in color-stabilized PVC components,as well as improved shelf life.

Example 22 Annealing after Doping

Post-doping annealing can be used to achieve a more uniform antioxidantdistribution. Unirradiated UHMWPE cubes were doped at 130° C. for 96hours by soaking in undiluted α-tocopherol. One cube was machined inhalves and microtomed. The microtomed sections were analyzed usinginfra-red microscopy, as described above in Example 9, to measure thevitamin E index as a function of depth away from one of the surfacesthat was free during doping. Subsequent to doping, other doped cubeswere annealed at 130° C. for increasing periods of time. The doped andannealed cubes were also analyzed using the infrared microscope todetermine the changes on the vitamin E index profile as a function ofannealing time. FIG. 3 shows the diffusion profiles measured in thedoped and also doped and annealed cubes. In the sample that has not beenannealed, the surface concentration was much higher than that for thebulk, but the sample that had been annealed for 100 hours at the sametemperature showed a nearly uniform profile. Therefore, annealing afterdoping can be used to increase the uniformity of the antioxidantdistribution throughout the host polymer. The temperature and time ofannealing can be tailored by carrying out a parametric analysis asdescribed herein.

Example 23 Sequences of Processing UHMWPE

UHMWPE can be doped with antioxidants at various stages, for example, asschematically shown in FIGS. 4 and 5.

It is to be understood that the description, specific examples and data,while indicating exemplary embodiments, are given by way of illustrationand are not intended to limit the present invention. Various changes andmodifications within the present invention will become apparent to theskilled artisan from the discussion, disclosure and data containedherein, and thus are considered part of the invention.

1-79. (canceled)
 80. A method for oxidative stabilization ofcross-linked ultrahigh molecular weight polyethylene (UHMWPE), whereinthe method comprises: (a) providing consolidated UHMWPE that has beenirradiated with ionizing radiation to form cross-links in the UHMWPE;(b) doping the consolidated UHMWPE from step (a) with an antioxidant bydiffusion, under ambient pressure, and at a temperature below themelting point of the UHMWPE; and (c) annealing the antioxidant-dopedconsolidated and cross-linked UHMWPE by heating at a temperature belowits melting point under ambient pressure, wherein the method provides aconsolidated and cross-linked UHMWPE that is oxidatively stable and canbe used in a medical implant.
 81. The method of claim 80, wherein thedoping is carried out by soaking the consolidated and cross-linkedUHMWPE in an antioxidant for about an hour to about 16 hours.
 82. Themethod of claim 80, wherein the doping is carried out by diffusion withan antioxidant under an inert gas atmosphere.
 83. The method of claim80, wherein the antioxidant is heated to about 100° C. or more and thedoping is carried out at 100° C. or more.
 84. The method of claim 80,wherein the antioxidant is Alpha- or delta-tocopherol, propyl, octyl, ordedocyl gallates, lactic, citric or tartaric acids, or any salt thereof,orthophosphates, or tocopherol acetate.
 85. The method of claim 80,wherein the antioxidant is vitamin E.
 86. A method for oxidativestabilization of cross-linked ultrahigh molecular weight polyethylene(UHMWPE), wherein the method comprises: a) providing consolidated UHMWPEthat has been irradiated with ionizing radiation to form cross-links inthe UHMWPE; (b) doping the consolidated UHMWPE from step (a) with anantioxidant by diffusion, under ambient pressure, and at a temperaturebelow the melting point of the UHMWPE; and (c) annealing theantioxidant-doped consolidated and cross-linked UHMWPE by heating at atemperature below its melting point under ambient pressure, wherein themethod provides a consolidated and cross-linked UHMWPE that isoxidatively stable and can be used in a medical implant; (d) machiningthe antioxidant-doped consolidated and cross-linked UHMWPE, therebyforming the medical implant comprising oxidatively stable UHMWPE; (e)packaging the medical implant comprising oxidatively stable UHMWPE; and(f) sterilizing the packaged medical implant by gamma radiation.
 87. Themethod of claim 86, wherein the gamma sterilization is carried out ininert gas or vacuum.
 88. The method of claim 86, wherein the doping iscarried out by soaking the consolidated and cross-linked UHMWPE in anantioxidant for about an hour to about 16 hours.
 89. The method of claim86, wherein the antioxidant is heated to about 100° C. or more and thedoping is carried out at 100° C. or more.
 90. The method of claim 86,wherein the doping is carried out by diffusion with an antioxidant underan inert gas atmosphere.
 91. The method of claim 86, wherein theantioxidant is Alpha- or delta-tocopherol, propyl, octyl, or dedocylgallates, lactic, citric or tartaric acids, or any salt thereof,orthophosphates, or tocopherol acetate.
 92. The method of claim 86,wherein the antioxidant is vitamin E.
 93. The method according to claim86, wherein the medical implant forms all or part of one selected fromthe group consisting of acetabular liner, shoulder glenoid, patellarcomponent, finger joint component, ankle joint component, elbow jointcomponent, wrist joint component, toe joint component, bipolar hipreplacements, tibial knee insert, tibial knee inserts with reinforcingmetallic and polyethylene posts, intervertebral discs, sutures, tendons,heart valves, stents, and vascular grafts.